When a controlled-release pharmaceutical formulation is administered to a living body, intra- or interindividual variation occurs frequently influenced by factors in the pharamceutical formulation or factors in the living body. One of the factors in the living body is a variation in a gastrointestinal transit time and as an optimum formulation for eliminating the factor, a multiple-units formulation is known (e.g., H. Bechgaad and G. H. Nielsen, Drug Devel. Ind. Pharm., 4, 53(1978)). This is a solid dosage form such as tablets, hard capsules, etc., that disintegrates in the gastrointestinal tract to form a number of units (e.g., microcapsules, microspheres, etc.,). A number of units distributes broadly in the gastrointestinal tract and an active substance is gradually released from these units.
Hitherto, there are known various materials and various production processes for obtaining an individual unit (e.g., microcapsule, microsphere, etc., ) of controlled-release multiple units pharmaceutical formulations containing an active substance.
For example, as the above-described materials, waxes, lipids, water-insoluble macromolecular materials, ion-exchange resins, etc., are known. Also, a production process of these individual units frequently requires a complicated and long step of preparing granules with an active substance and other material(s) and applying thereof enteric coating. In such a production process, there are frequently problems in the point of the production cost of products and the reproducibility of the dissolving characteristics of products.
Also, as a material forming a structure that is not easily disintegrated in the gastrointestinal tract, crystalline cellulose (the former name "microcrystalline cellulose") is known and a pharmaceutical formulation using crystalline cellulose in an amount of about 10 to 40% by weight based on the weight of the formulation is described in Japanese Patent Publication No. 5275/70. The above-metioned patent describes that the pharmaceutical formulation (the active substance of bis(o-benzoylthiamine)-disulfide) is a controlled-release one but enteric coating is necessary for further prolonging the releasing time. It is also described in the patent that the pharmaceutical formulation has a structure which does not easily disintegrate in the gastrointestinal tract, but in fact, it is known that if the amount of crystalline cellulose is about 10 to 40% by weight, the pharmaceutical formulation is insufficient in the point of strength. Furthermore, the formulation using the aforesaid amount of crystalline cellulose is also generally insufficient in the point of controlled-release of an active substance.
Furthermore, European Patent Publication No. 80341A.sup.2 describes an invention of "oral pharmaceutical controlled release multiple-units formulation". However, in the invention, "cores" are produced by a considerably complicated process and also enteric coating is applied thereto for obtaining controlled-release thereof. Moreover, the above-described pharmaceutical formulation does not disintegrate in the stomach and is prepared with the addition of disintegrants so that the coating is eroded and the core itself disintegrates in the small intestine.